title: Insulin-like growth factor binding protein-3 (IGFBP-3) plays a role in the anti-tumorigenic effects of 5-Aza-2'-deoxycytidine (AZA) in breast cancer cells.
abstract: Breast cancer progression is associated with loss of estrogen receptor (ER-α), often due to epigenetic silencing. IGFBP genes have consistently been identified among the most common to be aberrantly methylated in tumours. To understand the impact of losing IGFBP-3 tumour expression via DNA methylation, we treated four breast cancer cell lines (MCF-7, T47D, Hs578T and MDA-MB-231) with a DNA methyltransferase inhibitor, 5-Aza-2'-deoxycytidine (AZA) to determine IGFBP-3's role in the effects of AZA on total cell number and survival relative to changes in the ER. AZA induced cell growth inhibition, death and a reduction in the formation of colonies, despite increasing ER-α expression in ER-negative cells but reducing ER-α in ER-positive cells. Regardless of the differential effects on the ER-α, AZA consistently increased the abundance of IGFBP-3 and negating this increase in IGFBP-3 with siRNA reduced the AZA-induced growth inhibition and induction of cell death and virtually negated the AZA-induced inhibition of colony formation. With ER-α positive cells AZA increased the abundance of the tumour suppressor gene, p53 and induced demethylation of the IGFBP-3 promoter, whereas with ER negative cells, AZA epigenetically increased the transcription factor AP2-α, which when silenced prevented the increase in IGFBP-3. IGFBP-3 plays an important role in the anti-tumorigenic effects of AZA on breast cancer cells.
authors.affiliation: IGFs & Metabolic Endocrinology Group, University of Bristol, Learning & Research Building, Southmead Hospital, Bristol BS10 5NB, United Kingdom.
authors.forename: Li
authors.initials: L
authors.lastname: Zeng
authors.forename: Caroline
authors.initials: C
authors.lastname: Jarrett
authors.forename: Keith
authors.initials: K
authors.lastname: Brown
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Gillespie
authors.forename: Jeff M P
authors.initials: JM
authors.lastname: Holly
authors.forename: Claire M
authors.initials: CM
authors.lastname: Perks
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D019175:DNA Methylation; D000077209:Decitabine; D044127:Epigenesis, Genetic; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D034741:RNA, Small Interfering; D050656:Transcription Factor AP-2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D047628:Estrogen Receptor alpha; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D034741:RNA, Small Interfering; D050656:Transcription Factor AP-2; D016159:Tumor Suppressor Protein p53; D000077209:Decitabine; D001374:Azacitidine
keywords: AZA; Breast cancer; Cell survival; IGFBP-3